Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic a-cell. Although GLP-1 is established to be a cAMP-elevating agent, these studies demonstrate that protein kinase A (PKA) is not the only cAMP-binding protein by which GLP-1 acts. Instead, an alternative cAMP signaling mechanism has been described, one in which GLP-1 activates cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). Two variants of Epac are expressed in a-cells, and down regulation of Epac function diminishes stimulatory actions of GLP-1 on Ca2+ signaling and insulin secretion. Of particular note are new reports demonstrating that Epac couples a-cell cAMP production to the stimulation of fast Ca2+-dependent exocytosis. It is also reported that Epac mediates the cAMP-dependent mobilization of Ca2+ from intracellular Ca2+ stores. This is a process of Ca2+-induced Ca2+ release (CICR) and it generates an increase of [Ca2+]i that may serve as a direct stimulus for mitochondrial ATP production and secretory granule exocytosis. Such findings lead us to advance the Hypothesis that activation of Epac might explain how GLP-1 acts as a a -cell glucose-sensitizer. By facilitating a-cell glucose signaling, GLP-1 may increase the efficacy and potency of glucose as an insulinotropic stimulus. To test this Hypothesis, we will perform studies of human or rodent a-cells in which the glucose-dependent actions of GLP-1 are assessed in assays of mitochondrial ATP production, K-ATP ion channel regulation, and secretory granule exocytosis. Our long term goal is to elucidate the complex signal transduction properties of GLP-1 that explain its effectiveness as a blood glucose lowering agent when used for the treatment of type 2 diabetes mellitus.